B.S. in Biology, Grinnell College, Grinnell, Iowa, 1976Ph.D. in Microbiology, University of Tennessee, Knoxville, 1982Postdoctoral Training in Retrovirology, University of Alabama at Birmingham, 1982-1984

RESEARCH OVERVIEW:

The Wills lab is investigating several proteins of herpes simplex virus (HSV), all of which interact to form complexes within the infected cell and within the virion. The functions of these complexes are poorly understood. The following questions and answers provide some background.

WHAT IS HSV? It is one of eight human herpesviruses, all of which cause lifelong infections. Most people are infected with more than one. It is fortunate that these infections are usually kept under control by the immune systems of healthy individuals; however, in the immunosuppressed, these large DNA viruses are often lethal. With our population aging and organ transplants increasing, herpesviruses are going to cause even greater incidence of disease. Thus, it is important to learn more about these ubiquitous viruses so that new ways can be found to fight them.

WHAT IS THE NATURE OF THE VIRION?The structural proteins of herpesviruses are highly interconnected in the virion, but they are often classified according to their location within: 1) the nucleocapsid, 2) the surrounding but poorly-defined tegument layer, or 3) the outer, glycoprotein-containing lipid envelope. In the case of HSV, more than 40 different viral proteins have to be assembled, and understanding how they come together is a daunting task that is certain to require the continuing efforts of many investigators for decades to come. Nevertheless, the overall morphogenesis of the process is known. In brief, capsids are assembled and packaged with DNA in the nucleus, and some tegument proteins are attached soon afterwards. Nucleocapsids enter the cytoplasm by budding into the inner nuclear membrane and then fusing with the outer nuclear membrane. Additional tegument proteins are added before the capsid reaches the site of budding at Golgi-derived membranes, where yet more components of the tegument await in association with the cytoplasmic tails of the viral glycoproteins. Interactions between arriving capsid-tegument structures and tegument-glycoprotein complexes on the membrane result in envelopment and completed virions within vesicles. Finally, these vesicles move to the plasma membrane where they fuse, and the mature viruses are released. This is a very simple description of an extraordinarily complicated molecular process. But, because of its complexity, virus assembly events offer a large landscape for the discovery of novel antiviral targets as the molecular mechanisms emerge.

WHICH VIRAL PROTEINS ARE WE INVESTIGATING?We began investigating tegument protein UL11, which is peripherally associated with membranes and needed for cytoplasmic budding. We later discovered that UL11 interacts with tegument protein UL16, which is bound in some manner to the capsid. UL16 is also a binding partner of UL21, which is also capsid associated. More recently, we discovered that UL11 and UL16 bind to the portion of glycoprotein E (gE) that extends from the membrane into the cytoplasm and the virion. gE has long been known to be important for the spread of HSV in a manner that does not involve cell-free virions.

WHAT DO THESE INTERACTING PROTEINS DO?That is the big question. Homologs of UL11, UL16, and UL21 are found in all the herpesviruses, but their roles are largely unknown. Our studies have revealed that these tegument proteins are organized into an efficient molecular machine whose mechanism is triggered when the virus binds to its attachment receptors (heparan sulfate) on the host cell surface. In particular, we found that binding causes tegument protein UL16 to be released from the capsid as the tegument rearranges. This occurs prior to fusion of viral and host membranes; indeed, it occurs even when the virus binds to immobilized receptors on agarose beads. This is first example of an external signal being transmitted into any enveloped virus. We are still trying to identify all the parts of this machine. We want to know how are they assembled? How do they move? However, our studies also indicate that UL16 and its binding partners are involved in: a) virion budding in the cytoplasm, b) lateral spread of the virus in a cell-to-cell manner, and c) some sort of a function in the nucleus where most of UL16 accumulates during an infection.

Bibliographic

selected publications

Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications.
Faculty can login to make corrections and additions.